The present invention relates to novel functional polymer conjugates which inhibit one or more proteolytic and/or lipolytic enzymes. The polymer conjugates described herein are suitable for use in any context wherein proteolytic and/or lipolytic enzyme inhibition is indicated, inter alia, treatment of diaper rash.
Diaper rash is ubiquitous. It was once believed that contacting the skin with urine produced diaper rash, however, it is now understood that the irritation of tissue which manifests itself in xe2x80x9cdiaper rashxe2x80x9d is primarily caused by endogenic proteolytic and/or lipolytic enzymes, inter alia, trypsin, chymotrypsin, elastase, pancreatic lipase, which comprise human feces. However, skin irritation is not limited to enzymes which comprise feces, for example, menstrual fluids, nasal fluids, colostomy fluids, dandruff, wound healing may all provide a source of enzymes which produce irritation.
Proteolytic and lipolytic enzyme inhibitors are known. An example of effective inhibitors are xe2x80x9csuicide inhibitorsxe2x80x9d which irreversibly react with the active site of the target enzyme thereby destroying the enzyme""s ability to function. Reversible enzyme inhibitors, although not permanently inactivating the target enzyme, are also considered sufficiently effective to inhibit the effects of unwanted enzyme exposure. One drawback of low molecular weight enzyme inhibitors is their propensity to be readily absorbed through skin tissue, thereby entering into human cells wherein normal cell catabolism can be interrupted.
There is a long felt need to provide a barrier against the pernicious enzymes which act to irritate human skin, especially enzymes which produce diaper rash.
The present invention meets the aforementioned needs in that it has been surprisingly discovered that proteolytic and/or lipolytic enzyme inhibitors can be effectively delivered to human skin wherein said inhibitors can function as a barrier to enzyme activity thereby preventing diaper rash. The enzyme inhibitors of the present invention are polymer conjugates which have an enzyme inhibitor component and a functionalized polymer component.
The enzyme inhibitor component comprises a heterocyclic ring template and an enzyme targeting unit. The functionalized polymer component comprises a moiety which acts as an anchoring template for one or more enzyme inhibitors while providing a means for delivering the conjugate molecule to human skin. The enzyme inhibitor component is optionally, but preferably, linked to the functionalized polymer component by a linking group.
A first aspect of the present invention relates to an enzyme inhibiting polymer conjugate which is capable of inhibiting one or more proteolytic enzymes having the formula: 
wherein T is a heterocyclic unit; L is a linking group; [Poly] is a polymeric unit, i indicates the number of said heterocyclic units which comprise said conjugate and has the value of from 1 to 100; z is 0 or 1.
The present invention further relates to a process for preventing the formation of skin irritation which is due to the presence of proteolytic and/or lipolytic enzymes, said process comprises the step of contacting an effective amount of a polymer conjugate as described herein below to human skin.
These and other objects, features and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (xc2x0C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.
The present invention relates to the prevention of pernicious and otherwise unwanted skin conditions, inter alia, rash, irritation, which is caused by the contact of proteolytic and/or lipolytic enzymes with skin. Among the conditions which the present invention seeks to ameliorate is diaper rash. The present invention achieves the desired result by applying to the skin by a suitable means a sufficient amount of a polymer conjugate which inhibits the activity of one or more enzymes which are the cause of said unwanted skin condition.
The polymer conjugates of the present invention comprise an enzyme inhibitor component and a functionalized polymer component. The enzyme inhibitor component comprises a heterocyclic ring template and an enzyme targeting unit. Key to the effectiveness of the enzyme inhibitor is the fact that the inhibitor comprises xe2x80x9can enzyme specifying unitxe2x80x9d which has been modified.
The enzyme inhibitor component comprises a unit which has the role of either providing specificity for a particular enzyme or assists in deactivating the targeted enzyme.
The conjugates of the present invention further comprise a functionalized polymer component which acts as a delivery template for one or more enzyme inhibitors while providing a means for anchoring the conjugate molecule to human skin. The functionalized polymer component is typically an amphiphilic polymer which is capable of being directly attached to the enzyme inhibitor component or of being attached thereto by a linking unit. The polymer component also provides the conjugate with a source of increased molecular weight which acts to inhibit the absorption of the enzyme inhibitor into skin tissue. The polymer component also acts to facilitate formulation of the enzyme inhibitor into carriers or facilitates deposition of the conjugate directly to skin or by way of a substrate, diaper top sheet, inter alia, to which the conjugate is applied.
The conjugates of the present invention also optionally comprise a linking unit which serves to tether the enzyme inhibitor portion of the conjugate to the polymeric component. Although the polymer may be bonded directly to the enzyme inhibiting heterocycle, preferably a linking group is present to facilitate preparation and attachment of the polymer thereto.
The polymer conjugates of the present invention are utilized in an effective amount. For the purposes of the present invention the term xe2x80x9ceffective amountxe2x80x9d is defined herein as the amount necessary to provide a reduction in enzyme activity in at least one inhibition assay. Preferred assays which are described herein are, inter alia, xe2x80x9cFecal Protease Inhibition Assayxe2x80x9d, xe2x80x9cSkin Test of Inhibition of IL-1xcex1 Productionxe2x80x9d. Suitable tests also include tests which differentiate the specificity of said enzyme inhibitor, for example, which differentiate the particular proteases obstructed by said inhibitor.
Enzyme Inhibitor Component
The enzyme inhibitor component of the present invention comprises one or more heterocyclic moieties, designated herein as T units. The heterocyclic moiety is further characterized in that it comprises a unit (enzyme modulator) which interacts with one or more protease or lipase enzymes. Said heterocyclic moieties further optionally comprise one or more enzyme differentiating units, R.
The heterocyclic moieties of the present invention comprise 2 fused rings; an xe2x80x9cA ringxe2x80x9d which is common to all of the conjugates and a xe2x80x9cB ringxe2x80x9d which can vary widely and is further described herein below. The A ring has the formula: 
and is the ring which is preferably attached to the optional linking group or directly to the polymer component. It is this ring which is capable of reversibly reacting with a target enzyme via acylation. The acylating unit of the present heterocyclic moieties has a different configuration with respect to prior art acylating units. Key is the fact that the present invention provides for a conjugate which is not linked via the acylating unit itself and secondly the acylating unit is tied back into a ring. This key structural difference prevents the release of the acylating agent upon interaction with an enzyme or a hydrolyzing agent, inter alia, water, urine, body fluids.
The present invention overcomes any pejorative effects from pre-mature hydrolysis of the conjugate. For example, if the enzyme inhibitor component becomes prematurely detached from the polymer component, the inhibitor can then diffuse into healthy skin tissue. This has two immediate effects; the loss of active substrate and the possible infusion of an unwanted active into skin cells. This problem of detachment of the inhibitor component from the polymer component has been overcome by tying back the acylating unit into a ring.
The preferred acylating agent of the present invention is the ester carboxyl unit. A prior art polymer conjugate which is linked to an enzyme inhibitor via the ester carboxyl unit has the formula: 
and said conjugate is capable or reacting with a trypsin enzyme active site serine hydroxyl unit to displace the [Poly]-CH2Oxe2x80x94 unit which corresponds to the present invention as the polymer component. The effect of this reaction is the acylation of the enzyme active site serine hydroxyl moiety. Although specific to attack by the serine hydroxyl unit, this ester linkage is also potentially attacked by other hydrolyzing units. Hydrolysis of the above prior art inhibitor component from the polymer component prior to attack by the desired enzyme has the pejorative effect of potentially prematurely releasing the enzyme inhibitor from the enzyme. Indeed, if the enzyme inhibition takes place in a reversible manner, the inhibitor can be liberated from the enzyme and can diffuse into human skin tissue with potentially deleterious side-effects.
When the 4-guanidinobenzyl unit is incorporated into a polymer conjugate of the present invention, this results in a conjugate having the general formula: 
which provides resistance to fragmentation of the inhibitor component from the polymer conjugate while allowing the enzyme inhibitor component to be effectively delivered to enzyme active site via the acyl unit. Without wishing to be limited by theory, once the enzyme has interacted with the conjugate acylating unit, the species which remains will have the proposed formula: 
one advantage of which is the polymer component remains linked to the enzyme inhibitor component. If the enzyme interaction is reversible, then the resulting high molecular weight substrate will not be capable of diffusing into human skin tissue. In this manner linking units, especially linking units which are inextricably part of the ring system, can serve to attenuate the interaction of the inhibitor and a target enzyme.
The heterocyclic units of the present invention comprise units having the formula selected from the group consisting of: 
xi) and mixtures thereof;
xe2x80x83wherein X is selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CF2xe2x80x94, and mixtures thereof; and each D, E, F, and G is independently selected from the group consisting of xe2x80x94CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CF2xe2x80x94, and mixtures thereof.
Preferred heterocyclic units are selected from the group consisting of: 
xix) and mixtures thereof.
The preferred heterocycles of the present invention are units having the formula: 
more preferred units have the formula: 
most preferred units are the 4H-3,1-benzoxazin-4-one heterocycles having the formula: 
which are preferably linked to the polymeric component via the 2, 5, or 6 ring position. It will be noted by the formulator that only the exocyclic portion of the linking unit is rendered distinct from the heterocyclic ring system above. The examples herein above can effectively deliver a benzoic acid-like inhibitor, inter alia, 4-guanidinobenzoate, and part of the linking group is taken up as part of the benzoxazin-4-one ring system. Herein below only the exocyclic component of the linking groups are delineated, an the formulator is not restricted in using any part thereof to form other heterocycles which suitably deliver protease and/or lipase inhibitors.
The enzyme inhibition component further comprises one or more enzyme differentiating units, R. R units assist in attenuating the inhibitor/target enzyme interaction by, for example, providing a secondary sight of interaction between the polymer conjugates and the target enzymes. R units are:
a) hydrogen;
b) C1-C18 substituted or unsubstituted, linear or branched alkyl; preferably C1-C8 linear unsubstituted alkyl, inter alia, methyl and ethyl, especially when the enzyme inhibitor component comprises a benzoxazin-4-one moiety.
c) C3-C18 substituted or unsubstituted, cycloalkyl; preferably C6-C10 unsubstituted cycloalkyl;
d) C2-C18 substituted or unsubstituted, linear or branched alkenyl; preferably C10 and C15 branched alkenyl units derived from terpenes or other isoprene derived units;
e) C2-C18 substituted or unsubstituted, linear or branched alkynyl;
f) C6-C18 substituted or unsubstituted aryl; preferably phenyl, biphenyl, naphthyl and the like;
g) C2-C18 substituted or unsubstituted heterocyclic alkyl;
h) C3-C18 substituted or unsubstituted heterocyclic alkenyl;
i) alkylenearyl having the formula:
xe2x80x94(R1)nxe2x80x94R2
xe2x80x83wherein R1 is C1-C12 linear or branched alkylene, C2-C12 linear or branched alkenylene, or mixtures thereof; R2 is C6-C18 substituted or unsubstituted aryl, C3-C18 heteroaryl, or mixtures thereof; n is from 1 to 16; a preferred alkylenearyl unit comprises substituted benzyl units;
j) an amino unit having the formula:
xe2x80x94(CH2)mN(R3)2
xe2x80x83wherein each R3 is independently hydrogen, C1-C18 substituted or unsubstituted, linear, cyclic, or branched alkyl; m is from 0 to 10;
k) a quaternary ammonium unit having the formula: 
xe2x80x83wherein each R3 is independently hydrogen, C1-C18 substituted or unsubstituted, linear, cyclic, or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10;
l) a unit having the formula: 
xe2x80x83wherein R4 is hydrogen, C1-C4 alkyl, or mixtures thereof; R5 is hydrogen, C1-C4 alkyl, or mixtures thereof; R4 and R5 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferred is amidine;
m) a unit having the formula: 
xe2x80x83wherein R6 is hydrogen, C1-C4 alkyl, or mixtures thereof; R7 is hydrogen, C1-C4 alkyl, or mixtures thereof; R6 and R7 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferred are guanidine units and cyclic units, inter alia, imidazolinyl;
n) a unit having the formula:
xe2x80x94R8xe2x80x94R9
xe2x80x83wherein R8 is:
i) xe2x80x94(CH2)pxe2x80x94, wherein p is from 0 to 12;
ii) xe2x80x94C(O)xe2x80x94;
iii) xe2x80x94C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
iv) xe2x80x94C(X)R11C(X)xe2x80x94, wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
v) xe2x80x94C(X)NR10C(X)xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
vi) xe2x80x94C(X)NR10R11NR10C(X)xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
vii) xe2x80x94NR10C(X)xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
viii) xe2x80x94NR10C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
ix) xe2x80x94NR10C(X)R11NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
x) xe2x80x94NR10R11C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xi) xe2x80x94NR10C(X)R11C(X)Oxe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xii) xe2x80x94OC(X)R11C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xiii) xe2x80x94NR10C(X)NR11R11xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xiv) xe2x80x94R11NR10C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR10, and mixtures thereof;
xv) xe2x80x94R11NR10C(X)NR10R11xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xvi) xe2x80x94NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof;
xvii) xe2x80x94Oxe2x80x94;
xviii) xe2x80x94(R11)tC(X)(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1; X is oxygen, sulfur, NR10, and mixtures thereof;
xix) xe2x80x94(R11)tOC(O)(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xx) xe2x80x94(R11)tC(O)O(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxi) alkyleneoxyalkylene having the formula:
xe2x80x94(R12O)qR13xe2x80x94
xe2x80x83wherein R12 is C2-C6 linear or branched alkylene, substituted or unsubstituted phenylene; R13 is xe2x80x94(CH2)pxe2x80x94, wherein p is from 0 to 12; q is from 1 to 4;
xxii) xe2x80x94Sxe2x80x94;
xxiii) xe2x80x94(R11)tS(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxiv) xe2x80x94(R11)tS(O)(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxv) xe2x80x94(R11)tSO2(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxvi) or mixtures thereof;
R9is:
i) hydrogen;
ii) C1-C18 substituted or unsubstituted, linear or branched alkyl;
iii) C3-C18 substituted or unsubstituted, linear or branched cycloalkyl
iv) C2-C18 substituted or unsubstituted, linear or branched alkenyl;
v) C2-C18 substituted or unsubstituted, linear or branched alkynyl;
vi) C6-C18 substituted or unsubstituted aryl;
vii) C2-C18 substituted or unsubstituted heterocyclic alkyl;
viii) C3-C18 substituted or unsubstituted heterocyclic alkenyl;
ix) xe2x80x94OH;
x) xe2x80x94SO3M, wherein M is hydrogen or a water soluble cation;
xi) xe2x80x94OSO3M, wherein M is hydrogen or a water soluble cation;
xii) xe2x80x94NO2;
xiii) halogen selected from fluorine, chlorine, bromine, iodine, or mixtures thereof;
xiv) xe2x80x94C(Hal)3, wherein each Hal is fluorine, chlorine, bromine, iodine, or mixtures thereof;
xv) xe2x80x94COR14; wherein R14 is hydrogen, xe2x80x94OH, C1-C12 alkyl, C1-C12 alkoxy, or mixtures thereof; xe2x80x94N(R15)2, or mixtures thereof; each R15 is independently hydrogen, xe2x80x94OH, C1-C4 alkyl, or mixtures thereof;
xvi) xe2x80x94CH(OR14)2 wherein R4 is hydrogen, C1-C12 alkyl, or two R14 units can be taken together to form a ring having from 3 to 5 carbon atoms; or mixtures thereof;
xvii) a unit having the formula: 
xe2x80x83wherein R4 is hydrogen, C1-C4 alkyl, or mixtures thereof; R5 is hydrogen, C1-C4 alkyl, or mixtures thereof; R4 and R5 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms;
xviii) a unit having the formula: 
xe2x80x83wherein R6 is hydrogen, C1-C4 alkyl, or mixtures thereof; R7 is hydrogen, C1-C4 alkyl, or mixtures thereof; R6 and R7 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms;
xix) xe2x80x94NHOR16, wherein R16 is hydrogen; C1-C12 linear or branched alkyl; acyl having the formula xe2x80x94COR17, wherein R17 is C1-C4 alkyl; or mixtures thereof;
xx) a unit having the formula:
xe2x80x94CH=NOR16
xe2x80x83wherein R16 is hydrogen; C1-C12 linear or branched alkyl; C7-C22 linear or branched alkylenearyl; acyl having the formula xe2x80x94COR17, R17 is C1-C4 alkyl; or mixtures thereof;
xxi) an amino unit having the formula:
xe2x80x94(CH2)mN(R3)2
xe2x80x83wherein each R3 is independently C1-C18 substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10;
xxii) a quaternary ammonium unit having the formula: 
wherein each R3 is independently C1-C18 substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10;
o) two R units on the same carbon atom can be taken together to form a carbonyl unit or carbonyl unit equivalent, inter alia, Cxe2x95x90O, Cxe2x95x90NH; and
p) mixtures thereof.
Preferred R units according to the present invention include:
a) hydrogen;
b) C1-C8 linear unsubstituted alkyl, for example, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methyl hexyl, 2-ethyl, hexyl, Methyl and ethyl are especially preferred when the enzyme inhibitor component comprises a benzoxazin-4-one moiety.
c) C6-C10 unsubstituted cycloalkyl, for example cyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl;
d) C10 and C15 branched alkenyl units derived from terpenes or other isoprene derived units, for example, 3,7-dimethyl-6-octen-1-yl; 3,7-dimethyl-2,6-octadien-1-yl; 3,7-dimethyl-1 ,6-octadien-3-yl;
f) phenyl, naphthyl, 4-methoxyphenyl, 4-nitrophenyl, 4-(C1-C4 alkyl)phenyl;
g) C4-C6 substituted or unsubstituted heterocyclic alkyl; non-limiting examples of which include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolindinyl, 3-pyrrolidinyl, 2-piperazinyl, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, N-morpholinyl, and mixtures thereof;
h) C3-C18 substituted or unsubstituted heterocyclic alkenyl; 2-pyrrolyl, 3-pyrrolyl;
i) alkylenearyl having the formula:
xe2x80x94CH2xe2x80x94R2
xe2x80x83wherein R2 phenyl, substituted phenyl, pyridinyl, substituted pyridinyl;
j) an amino unit having the formula:
xe2x80x94N(R3)2
xe2x80x83wherein each R3 is independently hydrogen, methyl, ethyl, 2-hydroxyethyl, cyclopropyl; for example, methylamino, dimethylamino, ethylamino, diethylamino, dicyclopropyl;
l) a unit having the formula: 
xe2x80x83wherein R4 and R5 are each hydrogen, R4 and R5 is taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferably amidine, 2-pyridinyl, pyrimidinyl, imidazolyl;
m) a unit having the formula: 
n) a unit having the formula:
xe2x80x94R8xe2x80x94R9
xe2x80x83wherein R8 is:
i) xe2x80x94(CH2)pxe2x80x94, wherein p is from 0 to 12;
ii) xe2x80x94C(O)xe2x80x94;
xvi) xe2x80x94NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof;
xvii) xe2x80x94Oxe2x80x94;
xxi) alkyleneoxyalkylene having the formula:
xe2x80x94(R12O)qR13
xe2x80x83wherein R12 is C2-C6 linear or branched alkylene, substituted or unsubstituted phenylene; R13 is xe2x80x94(CH2)pxe2x80x94, wherein p is from 0 to 12; q is from 1 to 4;
xxii) xe2x80x94Sxe2x80x94;
xxvi) or mixtures thereof;
R9 is:
i) methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; preferably methyl when R8 is xe2x80x94Oxe2x80x94;
ii) cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 2,5-dimethylcyclopentyl;
v) phenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-aminobenzyl, 4-guanidiobenzyl;
vi) N-aziridinyl, 2-pyrrolindinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl;
viii) xe2x80x94OH, when the index p is from 1 to 4, preferably when p is 1;
ix) xe2x80x94SO3M when the index p is from 1 to 4, preferably when p is 1;
x) xe2x80x94OSO3M when the index p is from 2 to 4, preferably when p is 2;
xi) xe2x80x94NO2;
xii) chlorine, bromine, or mixtures thereof; more preferably chlorine;
xiii) xe2x80x94CF3;
xiv) xe2x80x94CO2R14; wherein R14 is hydrogen, xe2x80x94NH2, xe2x80x94N(CH3)2, or mixtures thereof;
xvii) xe2x80x94NHOR16, wherein R16 is hydrogen; C1-C12 linear or branched alkyl; acyl having the formula xe2x80x94COR17, wherein R17 is C1-C4 alkyl; or mixtures thereof;
xviii) a unit having the formula:
xe2x80x94CHxe2x95x90NOR16
xe2x80x83wherein R16 is hydrogen, or methyl; and
p) mixtures thereof.
For the purposes of the present invention the term xe2x80x9csubstituted or unsubstituted, linear or branchedxe2x80x9d is defined herein as the following. Alkyl chains which comprise, for example, a C1-C18 alkyl unit will have any combination of carbon atoms arranged in linear form or with one or more branching chains provided the total number of carbons is from 1 to 18 carbon atoms. By the term xe2x80x9csubstitutedxe2x80x9d is meant any unit which suitably replaces a hydrogen atom of a linear or branched chain, non-limiting examples of which include halogen, hydroxyl, nitro, amino, cyano, xe2x80x94CO2M, xe2x80x94SO3M, xe2x80x94OSO3M, wherein M is a water soluble cation. For alkenyl units, one or more double bonds may be present and said bonds may be conjugated or non-conjugated. Alkenyl units also include allenes. For aryl units, substituents may comprise alkyl units as well as halogen, etc.
R units can take any form which modulates the enzyme inhibition properties of the T unit. For example, R units under (i) above are alkylenearyl having the formula:
xe2x80x94(R1)nxe2x80x94R2
wherein R1 is C1-C12 linear or branched alkylene, C2-C12 linear or branched alkenylene, or mixtures thereof; R2 C6-C18 substituted or unsubstituted aryl, C3-C18 heteroaryl, or mixtures thereof; n is from 1 to 16. Non-limiting examples of suitable heteroaryl units are 5-member rings which have the formula: 
or a 6-member ring having the formula: 
wherein said unit can be attached at any carbon atom.
Non-limiting examples of heterocyclic units suitable for use in the present invention include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, and mixtures. The heterocyclic ring can be substituted, for example, 2-pyridinecarboxylic acid (picolinyl). The heterocyclic ring can be incorporated in any manner, for example, as a 2-pyridinyl unit (picolyl) or bonded to the heteroatom, for example, N-aziridinyl, N-pyrrolidinyl.
Conjugates of the present invention which are salts or salt-forming compounds will preferably have counter ions which facilitate delivery or formulation. For example, preferred cations include sodium, potassium, lithium, ammonium, alkylammonium, and the like. Preferred anions include halogen, preferably chlorine, methylsulfate, and the like. However, di-basic acids, inter alia, oxalic, fumaric, succinic, may be used to form deliverable salts as well.
Polymeric Component
The polymeric component of the present invention comprises units which provide the herein described conjugates with one or more properties which facilitate the delivery of the enzyme inhibitor to the required substrate.
The polymeric unit or the present invention, represented by [Poly]- can be bonded directly to the enzyme inhibiting component or can be attached by way of a linking unit.
The polymeric materials of the present invention comprise:
i) a polyalkyleneoxy unit having the formula:
R19(OR18)xxe2x80x94
xe2x80x83wherein R18 is C2-C12 linear alkylene, C3-C12 branched alkylene, phenylene, C7-C12 alkylenearylene, and mixtures thereof; R19 is hydrogen, C1-C18 substituted or unsubstituted, linear or branched alkyl; C3-C18 substituted or unsubstituted, linear or branched cycloalkyl; C2-C18 substituted or unsubstituted, linear or branched alkenyl; C2-C18 substituted or unsubstituted, linear or branched alkynyl; C6-C18 substituted or unsubstituted aryl; and mixtures thereof. The index x has the value of from about 10 to about 500. The polyalkyleneoxy unit may be a homopolymer, (e.g., all ethyleneoxy units), co-polymer (e.g., a mixture of ethyleneoxy and propyleneoxy units), or a block co-polymer. The average molecular weight of a polyalkyleneoxy polymeric unit according to the present invention is from about 400 daltons, preferably from about 1500 daltons, more preferably from about 3400 daltons to about 35,000 daltons, preferably to about 20,000 daltons, more preferably to about 10,000 daltons, most preferably to about 8000 daltons.
ii) a co-polymeric polyalkyleneoxy unit having the formula:
R19(OR18)x(OR20)yxe2x80x94
xe2x80x83wherein R18 is C2-C12 linear alkylene, C3-C12 branched alkylene, phenylene, C7-C12 alkylenearylene, and mixtures thereof; R19 is hydrogen, C1-C18 substituted or unsubstituted, linear or branched alkyl; C3-C18 substituted or unsubstituted, linear or branched cycloalkyl; C2-C18 substituted or unsubstituted, linear or branched alkenyl; C2-C18 substituted or unsubstituted, linear or branched alkynyl; C6-C18 substituted or unsubstituted aryl; and mixtures thereof; R20 is a unit selected from:
a) a unit having the formula: 
xe2x80x83wherein Rxe2x80x2 is hydrogen, methyl, allyl, hydroxyl, a linking group L which links an enzyme inhibiting component to the polymeric component as described herein below; xe2x80x94(CH2)zxe2x80x94J wherein J is selected from the group consisting of hydrogen, xe2x80x94CO2M, xe2x80x94OSO3M, xe2x80x94SO3M, xe2x80x94OPO3M, xe2x80x94PO3M, xe2x80x94N(Rxe2x80x3)2, xe2x80x94C(O)N(Rxe2x80x3)2, xe2x80x94NHC(xe2x95x90NH)NH2, xe2x80x94CCl13, xe2x80x94CF3, and mixtures thereof, wherein Rxe2x80x3 is hydrogen, C1-C4 alkyl, or mixtures thereof; M is a water soluble cation, preferably ammonium, sodium, or potassium; z is from 1 to 12, zxe2x80x2 is from 0 to 6; z +zxe2x80x2 is preferably less than 7. The index x has the value of from about 10 to about 500. The index y has the value of from about 10 to about 100.
b) a unit having the formula: 
xe2x80x83wherein Rxe2x80x2xe2x80x3 is C1-C4 alkyl, C1-C4 alkoxy, phenyl, a continuation of the chain by branching, or mixtures or mixtures; u has the value of from about 3 to 100. The molecular weight of a polymeric component which comprises a co-polymeric polyalkyleneoxy unit is such that the desired viscosity and solubility of the entire molecule fits the needs of the formulator. For example, units from (a) which comprise one or more linking units to enzyme inhibiting components may incorporate one or more hydrophilic units into the chain to increase the solubility of the final conjugate polymer. However, any of the polymers described herein can be random co-polymers or block co-polymers.
iii) a polysaccharide unit having the formula: 
xe2x80x83wherein R21 is hydrogen, C1-C4 alkyl, and mixtures thereof; the indices r and s are each independently from 0 to 100. The polysaccharide units of the present invention can be any mixture of 5 and 6-member ring sugar units, inter alia, sucrose, glucose, mannose, fructose.
iii) a polyamine unit having the formula: 
xe2x80x83R is C2-C12 linear alkylene, C3-C12 branched alkylene, and mixtures thereof; preferably R is ethylene, 1,3-propylene, and 1,6-hexylene, more preferred is ethylene. The indices j and k are such that the molecular weight of said polyamines does not exceed about 30,000 daltons. For example, for an entirely linear polyethyleneimine having a molecular weight of about 600 daltons, the index k is equal to 13 and j is equal to 0. For an entirely branched polyethyleneimine having a molecular weight of approximately 600 daltons, the index j is equal to 7. (This combination of indices results in a material having an average molecular weight of about 646 daltons, which, for the purposes of the present invention is a low molecular weight polyalkyleneimine.) The enzyme inhibiting component may be linked or directly bonded to any of the backbone nitrogen units.
The polymeric component of the present invention may be a mixture of one or more of the polymeric units described herein above. In addition, the formulator may attach to the polymeric component of the polymer conjugate as many linking units as necessary to deliver the required number of enzyme inhibiting components. One preferred permutation of admixtures of different components are star polymers as described in xe2x80x9cSynthesis of Star-Shaped Poly(ethylene oxide)xe2x80x9d, Y. Gnanou, et al., Makromolecular Chemistry, Vol. 189 (1988) pp. 2885-2892, U.S. Pat. No. 5,648,506 Desai et al., issued Jul. 15, 1997, each of which is incorporated herein by reference.
The preferred polymer or copolymer unit [Poly] of the present invention are polyalkyleneoxy unit having the formula:
R19(OR18)xxe2x80x94
and co-polymeric polyalkyleneoxy units having the formula:
R19(OR18)x(OR20)yxe2x80x94
wherein R19 is preferably methyl for conjugates which comprise one enzyme inhibitor component, R19 is preferably hydroxyethyl for conjugates comprising two enzyme inhibitor components. For the latter, the preferred [Poly] units have the formulae:
xe2x80x94OCH2CH2(OR18)xxe2x80x94 and xe2x80x94OCH2CH2(OR18)x(OR20)yxe2x80x94
R18 is preferably ethylene and R20 is preferably 2-propylene and when R18, OR19, and OR20 are taken together the [Poly] unit has a molecular weight of from about 500 daltons, preferably from about 1000 daltons, more preferably from about 2000 daltons, most preferably from about 3000 daltons to about 10,000 daltons, preferably to about 8,000 daltons, more preferably to about 7500 daltons. Preferred
R19(OR18)x(OR20)yxe2x80x94
units are copolymer having random polymer units, for example, using EO for ethyleneoxy and PO for propyleneoxy, units having a formula:
CH3(EO)xxe2x80x2(PO)yxe2x80x2(EO)xxe2x80x3(PO)yxe2x80x3(EO)xxe2x80x2xe2x80x3(PO)yxe2x80x2xe2x80x3xe2x80x94
wherein xxe2x80x2+xxe2x80x3+xxe2x80x2xe2x80x3+yxe2x80x2+yxe2x80x3+yxe2x80x2xe2x80x3 represent a copolymer having a molecular weight of from about 500 daltons, preferably from about 1000 daltons, more preferably from about 2000 daltons, most preferably from about 3000 daltons to about 10,000 daltons, preferably to about 8,000 daltons, more preferably to about 7500 daltons.
Non-limiting examples of suitable polyalkyleneoxy polymers for use in the present invention include polyethyleneglycol having an average molecular weight of 1500 daltons (PEG 1500), 4000 daltons (PEG 4000), polyethyleneglycol having an average molecular weight of 5000 daltons (PEG 5000), polyethyleneglycol methyl ether having an average molecular weight of 1500 daltons (MPEG 1500), polyethyleneglycol methyl ether having an average molecular weight of 4000 daltons (MPEG 4000), polyethyleneglycol methyl ether having an average molecular weigh of 5000 daltons (MPEG 5000), block co-polymers of polyethylene glycol and polypropylene glycol (EO/PO co-polymers, wherein said PO unit can be 1,2-propylene, 1,3-propylene, or mixtures thereof), and EO/PO/EO and PO/EO/PO co-polymers, for example Pluronics(copyright) available ex BASF. One important embodiment of the present invention relates to conjugates which comprise multiple enzyme inhibitor components. This can be done by the formulator to increase the relative amount of inhibitor on a per weight basis of conjugate or to deliver multiple inhibitors per conjugate. The following are non-limiting examples of polyhydroxy units which are suitable for this embodiment. 
Linking Units
The enzyme inhibiting polymer conjugates of the present invention optionally, but preferably, comprise one or more linking units, L. When the polymer component is bonded to more than one enzyme inhibiting units, the conjugate may comprise more than one linking unit. In addition, more than one type of linking unit may be present. For example, one type of linking unit may be convenient for one particular inhibitor component whereas a second unit is more compatible with a second type of heterocyclic enzyme inhibiting unit.
The linking units of the present invention may comprise any units capable of linking the enzyme inhibitor component to the polymer backbone. If the backbone is formed by random co-polymerization, the linking unit may be included. The linking group may be attached via xe2x80x9cgraftingxe2x80x9d to the polymer backbone. Units which may conveniently serve as linking units are amino acids which have a carboxyl end and an amine end and which are capable of easy assembly into polymeric units (peptides). One or more amino acids taken together are a preferred means for linking the polymer unit and the enzyme inhibitor unit.
Preferred linking units of the present invention have the formula:
xe2x80x94(R11)h{(X)j[C(X)]k(X)j(R11)h(X)j[C(X)]k(X)j}f(R11)hxe2x80x94
wherein the unit having the formula:
xe2x80x94{(X)j[C(X)]k(X)j(R11)h(X)j[C(X)]k(X)j}xe2x80x94
is preferably a repeatable unit, inter alia, amino acid, di-acid, wherein R11 is C1-C12 substituted or unsubstituted alkylene; C2-C12 substituted or unsubstituted alkenylene; C3-C12 cycloalkylene; substituted or unsubstituted aromatic; inter alia, 1,2-phenylene, 5-sulfo-1,3-phenylene, 1,4-phenylene; substituted or unsubstituted heterocyclic, non-limiting examples of which include benzimidazole, benzimidazolone, pyridine, piperazine, pyrroline, imidazoline, imidazole, morpholine, oxazole, tetrazole, 1H-indenedione, oxazoline, quinoline, isoquinoline, thiazine, thiazole, benzothiophene, all of which can be linked either through a carbon atom or a heteroatom. The R11 units can be substituted or unsubstituted with any of the herein above defined xe2x80x94R8R9 units. X is oxygen, sulfur, NR10 wherein R10 is hydrogen, C1-C4 alkyl, phenyl, or R10 can be taken as part of a ring bonded to another moiety in the linking group, for example, a propylene unit forming a ring between the nitrogen and R11 as in the formula: 
The indices h, j, and k are each independently 0 or 1. As indicated herein above amino acids are a suitable and a preferred class of linking units, either alone, in combination with other amino acids, or other R11 units. The index f has the value from 0 to 10. An example of a linking unit comprising a repeatable unit (amino acid) wherein the index f greater than 1 is a linking unit having the general formula:
xe2x80x94(R11)h{NHCH(CH3)C(O)}{NHCH2C(O)}(R11)hxe2x80x94
wherein a first repeatable unit is an alanine residue and a second repeatable u nit is a glycine residue. However, depending upon the value of the index f, any combination of repeatable units can be taken together to form a linking unit, for example, a linking unit having the formula: 
The preferred linking units of the present invention comprise one or more units selected from the group consisting of:
i) xe2x80x94(CH2)pxe2x80x94, wherein p is from 0 to 12;
ii) xe2x80x94C(O)xe2x80x94;
iii) xe2x80x94C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
iv) xe2x80x94C(X)R11C(X)xe2x80x94, wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
v) xe2x80x94C(X)NR10C(X)xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
vi) xe2x80x94C(X)NR10R11NR10C(X)xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
vii) xe2x80x94NR10C(X)xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
viii) xe2x80x94NR10C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
ix) xe2x80x94NR10C(X)R11NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
x) xe2x80x94NR10R11C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xi) xe2x80x94NR10C(X)R11C(X)Oxe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xii) xe2x80x94OC(X)R11C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xiii) xe2x80x94NR10C(X)NR10R11xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xiv) xe2x80x94R11NR10C(X)NR10xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xv) xe2x80x94R11NR10C(X)NR10R11xe2x80x94, wherein R10 is hydrogen, C1-C4 alkyl, or mixtures thereof; R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR10, and mixtures thereof;
xvii) xe2x80x94Oxe2x80x94;
xviii) xe2x80x94(R11)tC(X)(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1; wherein X is oxygen, sulfur, NR10, and mixtures thereof;
xix) xe2x80x94(R11)tOC(O)(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xx) xe2x80x94(R11)tC(O)O(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxi) xe2x80x94(R11)tOC(O)O(R11)txe2x80x94; wherein t is 0 or 1;
xxii) alkyleneoxyalkylene having the formula:
xe2x80x94(R12O)qR13xe2x80x94
xe2x80x83wherein R12 is C2-C6 linear or branched alkylene, substituted or unsubstituted phenylene; R13 is xe2x80x94(CH2)pxe2x80x94, wherein p is from 0 to 12; q is 1 or 2;
xxiii) xe2x80x94Sxe2x80x94;
xxiv) xe2x80x94(R11)tS(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxv) xe2x80x94(R11)tS(O)(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxvi) xe2x80x94(R11)tSO2(R11)txe2x80x94; wherein R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1;
xxvii) or mixtures thereof.
More preferred L units according to the present invention include:
i) xe2x80x94C(O)xe2x80x94;
ii) xe2x80x94C(O)NHxe2x80x94;
iii) xe2x80x94C(O)R11C(O)xe2x80x94, wherein R11 is methylene, ethylene, propylene, butylene, or mixtures thereof;
iv) xe2x80x94C(O)NHC(O)xe2x80x94;
v) xe2x80x94C(O)NHR11NHC(O)xe2x80x94 wherein R11 is methylene, ethylene, propylene, butylene, or mixtures thereof;
vi) xe2x80x94NHC(O)xe2x80x94;
vii) xe2x80x94NHC(O)NHxe2x80x94;
viii) xe2x80x94C(O)R11NHxe2x80x94, R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
ix) xe2x80x94NHR11C(O)xe2x80x94, R11 is C1-C12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
x) xe2x80x94NHxe2x80x94;
xi) xe2x80x94Oxe2x80x94;
xii) xe2x80x94R11OC(O)R11xe2x80x94; wherein R11 is methylene, ethylene, propylene, butylene, or mixtures thereof;
xiii) xe2x80x94R11C(O)OR11xe2x80x94; wherein R11 is methylene, ethylene, propylene, butylenes, or mixtures thereof;
xiv) or mixtures thereof.
The following are non-limiting examples of polymer conjugates according to the present invention.
Preferred polymer conjugates according to the present invention are the mono-inhibitors having the general formula:
[Poly]-(L)zxe2x80x94T
and the bis-inhibitors having the general formula:
Txe2x80x94(L)z-[Poly]-(L)zxe2x80x94T.
Non-limiting examples of preferred mono-inhibitors include: 
wherein L is O, NH, or mixtures thereof; and the index n has the value such that the polymer component derives from MPEG""s having an average molecular weight of 2000 daltons, 5000 daltons, 7000 daltons and mixtures thereof.
Non-limiting examples of preferred bis-inhibitors include: 
wherein L is O or NH, and the index n has the value such that the polymer component derives from PEG""s having an average molecular weight of 1500 daltons, 3400 daltons, 8000 daltons and mixtures thereof.
A preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein each R unit is hydrogen which is linked by an ethyleneimine unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula: 
Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein each R unit is hydrogen which is linked by an N-ethylene-Nxe2x80x2-phenylene urea unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula: 
Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein one R unit is guanidinyl which is linked by an N-ethylene-Nxe2x80x2-phenylene urea unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula: 
Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein one R unit is methyl which is linked directly to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula: 
Another preferred polymer conjugate comprises a thieno[3,2-d][1,3]oxazine-4-one heterocyclic unit wherein one R unit is methyl which is linked directly to a polyethylene-glycol polymer component having an average molecular weight of about 5000 daltons having the formula 